Molecular Signature of CAID Syndrome: Noncanonical Roles of SGO1 in Regulation of TGF-β Signaling and Epigenomics.
Abnormalities, Multiple
/ genetics
Adult
Cell Cycle Proteins
/ metabolism
DNA Methylation
/ genetics
Dermis
/ pathology
Epigenomics
Fibroblasts
/ metabolism
Gene Expression Profiling
Gene Ontology
Humans
Potassium Channels
/ metabolism
Proteome
/ metabolism
Reproducibility of Results
Signal Transduction
Syndrome
Transforming Growth Factor beta
/ metabolism
CAID Syndrome (Chronic Atrial and Intestinal Dysrhythmia)
Chronic Intestinal Pseudo-obstruction
Epigenetics
TGF-β Signaling
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2019
2019
Historique:
received:
23
05
2018
revised:
17
10
2018
accepted:
17
10
2018
pubmed:
12
2
2019
medline:
7
5
2019
entrez:
12
2
2019
Statut:
ppublish
Résumé
A generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic intestinal pseudo-obstruction and arrhythmias. Because CAID patients do not show phenotypes consistent with perturbation of known roles of SGO1, we hypothesized that noncanonical roles of SGO1 drive the clinical manifestations observed. To identify a molecular signature for CAID syndrome, we achieved unbiased screens in cell lines and gut tissues from CAID patients vs wild-type controls. We performed RNA sequencing along with stable isotope labeling with amino acids in cell culture. In addition, we determined the genome-wide DNA methylation and chromatin accessibility signatures using reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing. Functional studies included patch-clamp, quantitation of transforming growth factor-β (TGF-β) signaling, and immunohistochemistry in CAID patient gut biopsy specimens. Proteome and transcriptome studies converge on cell-cycle regulation, cardiac conduction, and smooth muscle regulation as drivers of CAID syndrome. Specifically, the inward rectifier current, an important regulator of cellular function, was disrupted. Immunohistochemistry confirmed overexpression of Budding Uninhibited By Benzimidazoles 1 (BUB1) in patients, implicating the TGF-β pathway in CAID pathogenesis. Canonical TGF-β signaling was up-regulated and uncoupled from noncanonical signaling in CAID patients. Reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing experiments showed significant changes of chromatin states in CAID, pointing to epigenetic regulation as a possible pathologic mechanism. Our findings point to impaired inward rectifier potassium current, dysregulation of canonical TGF-β signaling, and epigenetic regulation as potential drivers of intestinal and cardiac manifestations of CAID syndrome. Transcript profiling and genomics data are as follows: repository URL: https://www.ncbi.nlm.nih.gov/geo; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601.
Sections du résumé
BACKGROUND & AIMS
A generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic intestinal pseudo-obstruction and arrhythmias. Because CAID patients do not show phenotypes consistent with perturbation of known roles of SGO1, we hypothesized that noncanonical roles of SGO1 drive the clinical manifestations observed.
METHODS
To identify a molecular signature for CAID syndrome, we achieved unbiased screens in cell lines and gut tissues from CAID patients vs wild-type controls. We performed RNA sequencing along with stable isotope labeling with amino acids in cell culture. In addition, we determined the genome-wide DNA methylation and chromatin accessibility signatures using reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing. Functional studies included patch-clamp, quantitation of transforming growth factor-β (TGF-β) signaling, and immunohistochemistry in CAID patient gut biopsy specimens.
RESULTS
Proteome and transcriptome studies converge on cell-cycle regulation, cardiac conduction, and smooth muscle regulation as drivers of CAID syndrome. Specifically, the inward rectifier current, an important regulator of cellular function, was disrupted. Immunohistochemistry confirmed overexpression of Budding Uninhibited By Benzimidazoles 1 (BUB1) in patients, implicating the TGF-β pathway in CAID pathogenesis. Canonical TGF-β signaling was up-regulated and uncoupled from noncanonical signaling in CAID patients. Reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing experiments showed significant changes of chromatin states in CAID, pointing to epigenetic regulation as a possible pathologic mechanism.
CONCLUSIONS
Our findings point to impaired inward rectifier potassium current, dysregulation of canonical TGF-β signaling, and epigenetic regulation as potential drivers of intestinal and cardiac manifestations of CAID syndrome. Transcript profiling and genomics data are as follows: repository URL: https://www.ncbi.nlm.nih.gov/geo; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601.
Identifiants
pubmed: 30739867
pii: S2352-345X(18)30157-7
doi: 10.1016/j.jcmgh.2018.10.011
pmc: PMC6369230
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
Potassium Channels
0
Proteome
0
SGO1 protein, human
0
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
411-431Subventions
Organisme : CIHR
ID : 366129
Pays : Canada
Investigateurs
Gregor Andelfinger
(G)
Jeroen Bakkers
(J)
Bart Loeys
(B)
Michel Pucéat
(M)
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Clin Gastroenterol Hepatol. 2005 May;3(5):449-58
pubmed: 15880314
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Genes Immun. 2013 Jan;14(1):1-6
pubmed: 23190643
Oncogene. 2002 Aug 12;21(35):5380-7
pubmed: 12154400
Nat Genet. 2014 Nov;46(11):1245-9
pubmed: 25282101
Annu Rev Physiol. 1996;58:363-94
pubmed: 8815800
Neurogastroenterol Motil. 2007 Jun;19(6):440-52
pubmed: 17564625
Nature. 2012 Sep 13;489(7415):313-7
pubmed: 22885700
Structure. 2011 Nov 9;19(11):1625-34
pubmed: 22032967
Nature. 2008 Feb 14;451(7180):796-801
pubmed: 18235444
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Cell Stem Cell. 2010 May 7;6(5):479-91
pubmed: 20452322
BMC Bioinformatics. 2009 Jul 27;10:232
pubmed: 19635165
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Crit Rev Eukaryot Gene Expr. 2011;21(4):303-11
pubmed: 22181700
Basic Res Cardiol. 2012 Nov;107(6):299
pubmed: 22976005
Gastroenterology. 2012 Dec;143(6):1482-1491.e3
pubmed: 22960657
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Cell Cycle. 2012 Feb 1;11(3):479-88
pubmed: 22262168
Nat Protoc. 2006;1(6):2650-60
pubmed: 17406521
Neurology. 2009 Mar 24;72(12):1103-5
pubmed: 19307547
Cell Death Dis. 2016 Aug 04;7(8):e2321
pubmed: 27490926
Circ Res. 2015 Feb 27;116(5):836-45
pubmed: 25608527
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
Genome Res. 2010 May;20(5):578-88
pubmed: 20219941
Am J Hum Genet. 2007 Apr;80(4):751-8
pubmed: 17357080
Sci Signal. 2015 Jan 06;8(358):ra1
pubmed: 25564677
Science. 1999 Jan 29;283(5402):689-92
pubmed: 9924029
Mol Cell Proteomics. 2011 Aug;10(8):M110.003699
pubmed: 21586754
Sci Rep. 2015 Nov 19;5:16803
pubmed: 26581180
Circulation. 2008 Mar 25;117(12):1583-93
pubmed: 18332262
Cytoskeleton (Hoboken). 2015 Jun;72(6):257-67
pubmed: 26147585
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Bioinformatics. 2009 May 1;25(9):1105-11
pubmed: 19289445
Genome Biol. 2012 Oct 03;13(10):R87
pubmed: 23034086
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Mol Cells. 2007 Apr 30;23(2):175-81
pubmed: 17464194
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Nature. 2001 Feb 15;409(6822):860-921
pubmed: 11237011
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8309-14
pubmed: 18550811
J Physiol. 2018 Feb 1;596(3):379-391
pubmed: 29205356
Gastroenterology. 2015 Apr;148(4):771-782.e11
pubmed: 25575569
Int J Cardiol. 2010 Sep 3;143(3):405-13
pubmed: 19394095
Cancer Cell. 2014 Oct 13;26(4):577-90
pubmed: 25263941
Nat Rev Genet. 2012 May 29;13(7):484-92
pubmed: 22641018
J Biol Chem. 1987 Jan 5;262(1):116-22
pubmed: 2947901
Am J Hum Genet. 2012 Jun 8;90(6):1014-27
pubmed: 22633399
Nucleic Acids Res. 2014 Apr;42(8):e69
pubmed: 24561809
Cell Host Microbe. 2015 Dec 9;18(6):723-35
pubmed: 26651948